Cocoa Flavanols: Nutraceuticals with Promising Pharmacological Properties

Every now and then medical research catches up with traditional medical uses of plants and herbs.

Then, of course, the desire of the researchers is to create a patentable drug from that research.

But women (and men) throughout history can tell you that Chocolate has magical properties. So great are the benefits of chocolate that poems have been written in tribute, songs sung in honor, and several holidays would not be complete without it, our recent Easter and Valentines Days included.

So to see research into the chemical constituents of chocolate is highly interesting to me. Since I tend to use food as my first line of change with any patient, whenever a food can be tasty, plentiful and desired, it is easy to prescribe.

That’s why I love xylitol gum for fluid in the middle ear, pumpkin seeds to increase a patient’s zinc levels and dark chocolate for hypertension and cardiovascular health.

Here are some excerpts from a recent article Cocoa Flavanols: Nutraceuticals with Promising Pharmacological Properties
All Italics are mine.

Flavonoids belong to a group of natural substances with phenolic structures built around a core flavone structure and are found in plants and food products such as wine (and Chocolate).[1]

Flavonoids protect tissues from the adverse effects of reactive oxygen species (ROS).[7]

flavonoids can also act as anti-inflammatory agents due to their capacity to reduce leucocyte adhesion and activation.[10,11] (leucocytes are white blood cells)

Flavonoids exert anti-clotting effects due to their capacity to inhibit platelet aggregation[13] and the procoagulant effects of Reactive oxygen species. (ie. less clotting formation in the blood vessels in the presence of oxidative damage)

Flavonoids are potent stimulators of endothelial Nitrous Oxide Species; the resultant production of Nitrous Oxide produces vasodilation, anti-coagulant, and anti-adhesion effects.[7]

In the context of cardiovascular pathology, the sum of all flavonoid actions can be seen as generally reducing the chances of either developing disease or mitigating ongoing pathological processes.

Cacao Beans are a Source of Flavonoids and Numerous Other Compounds

The main type of flavonoids present in cacao beans are flavanols. Cacao beans, from which chocolate is made, come from the fruit of the tree, Theobroma cacao (Figure 2), which grows mainly in subtropical regions of world. As the name theobroma (“food of the gods”) suggests, the beans contain the xanthine theobromine in significant quantity, ~1.2% by weight, as well as flavonoids and nearly 400 other identified compounds.

Traditional processing methods that yield “modern chocolate,” especially alkalinization (dutching, to mellow flavor), strips flavanols from cocoa.[14] The bitterness from cacao mostly comes from flavanols. With the emerging recognition of the beneficial effects of flavanols there has been a shift in commercial production towards chocolate forms with high flavanol content.[14] Cocoa powder can contain as little as 10% fat and has up to 6% by weight flavanols. It also has minerals (Mg, Cu, K and Ca), protein, and fiber in modest amounts. The main flavanols present in the cocoa powder are catechins and epicatechins in either monomeric or multimeric (procyanidin) forms.[15] (Figure 3) Special cocoa formulations developed by industry now contain up to 10% of cocoa flavanols.[16] Cocoa butter accounts for up to 57% of the dry weight of a bean. The predominant fatty acids are stearic, palmitic, oleic and linoleic.

The ingestion of cocoa butter appears to have neutral effects on the blood lipid profile of humans and on platelet aggregation
.[15] Plant sterols including sitosterol and stigmasterol are present in cocoa butter in very small amounts, and appear to have little or no impact on cholesterol absorption.[15] Thus, in spite of having saturated fat present as a constituent, cocoa butter has little or no impact on blood lipid profiles in humans.

Cacao beans held great prominence in the daily lives of Mesoamerican Indians. According to the Mayan and Mexica religions, cacao had divine origins as the god Quetzalcoatl discovered cacao. Cacao was prepared only as a beverage and was a food reserved for adult males with prominent roles in society. Columbus’ crew captured a canoe that contained mysterious-looking “almonds,” later identified as currency in Mesoamerica. Diaz del Castillo, an officer with Hernan Cortez wrote: “From time to time the men of Montezuma’s guard brought him, in cups of pure gold, a drink made from the cocoa-plant, which they said he took before visiting his wives.” The Spaniards noted that the Aztecs could walk long distances without incurring fatigue and suspected a role for the cacao beverage. Historical Mesoamerican documents include instructions for the medicinal use of cacao.[17] Ceramic pieces obtained from the Maya note a warrior in cacao armor as the Mayan’s would believe that cacao would make you stronger and invincible. Modern claims for the efficacy of cocoa, based on current biomedical research, are a bit more modest but still quite impressive, as described below.

Cocoa and Cardiovascular Protection

Interest in the cardiovascular effects of cocoa flavanols reemerged recently by the observation that Kuna Indians living off the coast of Panama have a very low incidence of hypertension and no increase in blood pressure as they age. The factors involved are clearly environmental since protection is lost upon migration into the mainland.[18] The island Kuna drink large amounts of home-prepared cocoa, rich in flavanols, whereas Kuna on the mainland consume commercial cocoa that is mostly devoid of flavonoids.[16] Having discounted body weight, exercise, alcohol intake and other relevant factors as mediators of cardiovascular protection, researchers noted that the Kuna had a renal hemodynamic status suggestive of high NO levels.[16] Hollenberg et al., developed the hypothesis that the consumption of flavonoid-rich cocoa would promote vasodilation secondary to increased NO synthesis.[16] These data were confirmed in individuals consuming flavonoid-rich cocoa and the effect was reversed by the NO synthesis inhibitor L-NAME.[19,20]

Cocoa powder and cocoa extracts have been shown to exhibit greater antioxidant capacity than many other flavanol-rich foods and food extracts, such as green tea and blueberries.[14] Antioxidant effects are evident immediately when compounds are used in vitro or in vivo at concentrations >0.02 mM. Among healthy humans, inhibition of LDL oxidation was reported within 2 h after the consumption of a flavanol-rich cocoa.[22]

Diabetes-induced cataracts … were decreased in rats given cocoa liquor.[25]

In humans, the consumption of a flavonoid-rich chocolate demonstrated increased plasma antioxidant capacity that peaked 2 h after consumption and returned to baseline by 6 h.[26,27]
Cocoa flavanols also possess other beneficial effects that are apparent at relatively low doses.[14] Grassi et al. demonstrated[28] that the ingestion of dark chocolate for 15 days (100 g/day containing 88 mg of flavanols or ~1.2 mg/kg/day) decreased blood pressure and serum LDL cholesterol, improved flow-mediated dilation, and improved insulin sensitivity in hypertensive patients. These effects were absent in patients taking isocaloric amounts of white chocolate. These results are quite striking given that the beneficial effects were noted not only on blood pressure but also on other cardiovascular risk factors such as LDL levels and insulin sensitivity.

The beneficial effects of cocoa have also been noted in the setting of underlying disease, such as aging-induced vascular dysfunction,[30] endothelial dysfunction in smokers,[31] and in postmenopausal women.[32] Interestingly, the sustained decrease in blood pressure in hypertensive patients as seen by Grassi et al.[28] required the prolonged intake of dark chocolate. (Like I said, simple to prescribe)

On the basis of the evidence presented above, which includes epidemiological (Kuna Indians), clinical (studies in humans) and pre-clinical (using animal models), one may reasonably propose that cocoa flavanols hold promise as nutraceuticals with potent cardiovascular protective properties. Their regular consumption in forms that are low in calories should be considered, given the compelling evidence that has emerged.


1. Middleton, E., Jr., Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol, 1998. 439: p. 175-82.
2. Formica, J.V. and W. Regelson, Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol, 1995. 33(12): p. 1061-80.
3. Baur, J.A., et al., Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 2006.
4. Hertog, M.G., et al., Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med, 1995. 155(4): p. 381-6.
5. Knekt, P., et al., Flavonoid intake and coronary mortality in Finland: a cohort study. Bmj, 1996. 312(7029): p. 478-81.
6. Rice-Evans, C.A., N.J. Miller, and G. Paganga, Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med, 1996. 20(7): p. 933-56.
7. Nijveldt, R.J., et al., Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr, 2001. 74(4): p. 418-25.
8. Shoskes, D.A., Effect of bioflavonoids quercetin and curcumin on ischemic renal injury: a new class of renoprotective agents. Transplantation, 1998. 66(2): p. 147-52.
9. Hanasaki, Y., S. Ogawa, and S. Fukui, The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radic Biol Med, 1994. 16(6): p. 845-50.
10. Friesenecker, B., et al., Oral administration of purified micronized flavonoid fraction suppresses leukocyte adhesion in ischemia-reperfusion injury: in vivo observations in the hamster skin fold. Int J Microcirc Clin Exp, 1994. 14(1-2): p. 50-5.
11. Friesenecker, B., A.G. Tsai, and M. Intaglietta, Cellular basis of inflammation, edema and the activity of Daflon 500 mg. Int J Microcirc Clin Exp, 1995. 15 Suppl 1: p. 17-21.
12. Ferrandiz, M.L., et al., Effect of bakuchiol on leukocyte functions and some inflammatory responses in mice. J Pharm Pharmacol, 1996. 48(9): p. 975-80.
13. Osman, H.E., et al., Grape juice but not orange or grapefruit juice inhibits platelet activity in dogs and monkeys. J Nutr, 1998. 128(12): p. 2307-12.
14. Keen, C.L., et al., Cocoa antioxidants and cardiovascular health. Am J Clin Nutr, 2005. 81(1 Suppl): p. 298S-303S.
15. Steinberg, F.M., M.M. Bearden, and C.L. Keen, Cocoa and chocolate flavonoids: implications for cardiovascular health. J Am Diet Assoc, 2003. 103(2): p. 215-23.
16. Fisher, N.D. and N.K. Hollenberg, Flavanols for cardiovascular health: the science behind the sweetness. J Hypertens, 2005. 23(8): p. 1453-9.
17. Dillinger, T.L., et al., Food of the gods: cure for humanity? A cultural history of the medicinal and ritual use of chocolate. J Nutr, 2000. 130(8S Suppl): p. 2057S-72S.
18. Hollenberg, N.K., et al., Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension, 1997. 29(1 Pt 2): p. 171-6.
19. Fisher, N.D., et al., Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens, 2003. 21(12): p. 2281-6.
20. Heiss, C., et al., Vascular effects of cocoa rich in flavan-3-ols. Jama, 2003. 290(8): p. 1030-1.
21. Keen, C.L., Chocolate: food as medicine/medicine as food. J Am Coll Nutr, 2001. 20(5 Suppl): p. 436S-439S; discussion 440S-442S.
22. Kondo, K., et al., Inhibition of LDL oxidation by cocoa. Lancet, 1996. 348(9040): p. 1514.
23. Baba, S., et al., Cocoa powder enhances the level of antioxidative activity in rat plasma. Br J Nutr, 2000. 84(5): p. 673-80.
24. Orozco, T.J., J.F. Wang, and C.L. Keen, Chronic consumption of a flavanol- and procyanindin-rich diet is associated with reduced levels of 8-hydroxy-2′-deoxyguanosine in rat testes. J Nutr Biochem, 2003. 14(2): p. 104-10.
25. Osakabe, N., et al., Ingestion of proanthocyanidins derived from cacao inhibits diabetes-induced cataract formation in rats. Exp Biol Med (Maywood), 2004. 229(1): p. 33-9.
26. Lotito, S.B., et al., Influence of oligomer chain length on the antioxidant activity of procyanidins. Biochem Biophys Res Commun, 2000. 276(3): p. 945-51.
27. Rein, D., et al., Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. J Nutr, 2000. 130(8S Suppl): p. 2109S-14S.
28. Grassi, D., et al., Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension, 2005. 46(2): p. 398-405.
29. Schroeter, H., et al., (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A, 2006. 103(4): p. 1024-9.
30. Fisher, N.D. and N.K. Hollenberg, Aging and vascular responses to flavanol-rich cocoa. J Hypertens, 2006. 24(8): p. 1575-80.
31. Heiss, C., et al., Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol, 2005. 46(7): p. 1276-83.
32. Wang-Polagruto, J.F., et al., Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women. J Cardiovasc Pharmacol, 2006. 47 Suppl 2: p. S177-86; discussion S206-9.
33. Diebolt, M., B. Bucher, and R. Andriantsitohaina, Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. Hypertension, 2001. 38(2): p. 159-65.
34. Leikert, J.F., et al., Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation, 2002. 106(13): p. 1614-7.

Francisco Villarreal, Professor of Medicine, UCSD School of Medicine, San Diego

AccessMedicine from McGraw-Hill. 2009; ©2009 The McGraw-Hill Companies
All rights reserved. From Tintinalli’s Emergency Medicine

So we can all be assured that eating cocoa and chocolate is a good dietary choice for our cardiovascular health.
But, beware, we want to avoid Dutch process cocoa that is alkalinized and use dark chocolate for our bodies best support.

So here is a recipe that I love for Bittersweet Chocolate Sandwich Cookies.

Bittersweet Chocolate Sandwich Cookies

1 cup brown rice flour
1 cup teff flour (dark works fine)
1/4 cup sweet rice flour
1/2 cup unsweetened cocoa powder (preferably 70 % or higher cocoa solids)
1/2 t. baking powder
1/2 t. salt
1/2 teaspoon xanthan gum

3/4 cup (1 1/2 sticks) unsalted butter or earth balance shortening sticks for casein-free cookies- softened
3/4 cup granulated sugar
5 oz. fine-quality semisweet or bittersweet chocolate (not unsweetened), melted and cooled. You can use chocolate chips if desired.
1 t. vanilla
Whisk together flours, cocoa, baking powder, and salt in a bowl until combined.

Beat together butter, melted chocolate and granulated sugar in a large bowl with an electric mixer at medium-high speed until fluffy, about 2 minutes in a stand mixer (preferably fitted with paddle attachment) or 4 minutes with a handheld.
Add vanilla, beating until combined. Reduce speed to low, then add flour mixture and mix until combined well. On plastic wrap, place dough and roll into a long log, chill dough until firm, about 30 minutes.

Put oven racks in upper and lower thirds of oven and preheat oven to 325˚F.

Slice 1/2 inch pieces of dough, arranging them 2 inches apart on parchment lined baking sheets.

Bake cookies, switching position of sheets halfway through baking, 8 to 10 minutes total, then transfer with a metal spatula to racks to cool completely. When done the cookies will be firm at the edges but still dent in the center.
Just slide the parchment piece onto the rack and let cool completely

Using ganache, pipe 1-2 tablespoons of filling on one half of sandwich cookie, top with second half.

Ganache- dairy free
6 oz fine quality chocolate- semisweet
3 tablespoons unsweetened vanilla soymilk or if you can use dairy use heavy cream

Blend together in bowl, then beat till fluffy. Place in piping bag or zip lock.


  1. says

    I think I am going to go eat some chocolate! The recipe looks amazing. I was just wondering how to make a dairy free ganache.